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Pituitary Disorders
Figure 3: Inheritance of Familial Isolated
pituitary disease.
7,9,11,13,16–24
About 2% of these patients have an AIP mutation
Pituitary Adenoma
in their DNA (27 of 1,100 sporadic pituitary adenoma patients). Most
patients with AIP mutations in the ‘apparently’ sporadic cohort have a
diagnosis of acromegaly, but there are two reported cases of mutations in
Affected Unaffected
patients with Cushing’s disease.
11,19
father mother
Other Tumors in Familial Isolated
Pituitary Adenoma Patients
In our cohort of FIPA families, non-pituitary tumors occur in families with
affected patients or obligate AIP mutation carriers: lipomas, breast,
Unaffected
thyroid, testicular, renal and bone marrow tumors, anaplastic
Affected
astrocytomas, primitive neuroectodermal tumors
9
and ependymomas
Carrier with no
manifestation
(also unpublished data). The association of FIPA with adrenal
carcinoma
25,26
has also been reported. However, it is unclear whether any
of these tumors are part of the FIPA syndrome; further studies are
necessary to clarify this.
AIP Mutations in Other Tissues
The role of somatic AIP mutations has previously been studied in the
pathogenesis of common cancers (373 colorectal cancers, 82 breast
cancers, and 44 prostate tumor samples)
27
and 79 endocrine tumors
Carrier Unaffected Unaffected Affected
(26 thyroid lesions, 19 adrenal lesions, 16 carcinoids, eight
son with daughter son daughter
parathyroid lesions, four paragangliomas, four pancreatic endocrine
no manifestation
tumors, and two adenocarcinoids).
21
No somatic mutations were
Patients with familial isolated pituitary adenoma inherit an abnormal copy of the gene causing
found, suggesting that AIP is not strongly involved in tumorigenesis in
the disease from one of their parents. In some patients this will result in the development of a
pituitary adenoma (the disease is manifested), while in others it will not cause any disease, but
these tumor types.
the gene can be passed on to the next generation.
Figure 4: Example of Familial Isolated Pituitary
Tumor-suppressor Role for AIP
Adenoma Family Trees
Based on clinical data, it has been suggested that FIPAs are caused by
a heterozygous germline mutation in a tumor-suppressor gene. Our
group has recently captured unique functional data on AIP consistent
with a tumor-suppressor role for AIP.
9
Cells were transfected with the
AIP gene and showed reduced proliferation. On the other hand, when
the cell’s own AIP was knocked out, cell proliferation increased.
Mixed acromegaly/
Practical Relevance to the Clinical
Acromegaly family
prolactinoma family
Endocrinologist of These Emerging Data
About Familial Isolated Pituitary Adenomas
Identifying AIP mutations in patients and carriers is of great clinical
importance. Patients with AIP mutations tend to have a more aggressive
disease, and treatment can be extremely challenging if diagnosis is late.
Genetic testing of relatives of patients with AIP mutations may lead to
Mixed acromegaly/NFPA family
Prolactinoma family
earlier pituitary tumor detection, thus allowing treatment at an earlier
stage. All patients with a family history of pituitary adenoma and no
suspicion of MEN1 and Carney complex should undergo genetic
counseling and testing for AIP.
If a mutation is found, family members should be screened for the
NFPA family
mutation. Carriers should be tested regularly for clinical symptoms
Mixed acromegaly/Cushing’s family
and signs and should undergo biochemical and (if necessary) imaging
investigations, given that heterologous tumors can occur within
Gigantism Acromegaly Carrier Prolactinoma Not affected
families but keeping in mind that incidental tumors of the pituitary are
Non-functioning pituitary adenoma (NFPA) Cushing’s disease
common. If no AIP mutation is found, all family members with a 50%
Heterogeneity of pituitary tumors is found in families with familial isolated pituitary adenoma.
chance of inheriting the disease should be regularly tested. Currently,
The most common tumor types seen are somatotroph and lactotroph adenomas. In the current
we are searching for gene(s) causing the disease in AIP-negative
examples the gene and the mutations causing the disease have not been found for the
prolactinoma, NFPA, and mixed families; therefore, the unaffected carriers cannot be shown.
families and would like patients with a family history of pituitary
106 US ENDOCRINOLOGY
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